Cardiovascular disease represents a major cause of reduced lifespans in people with schizophrenia, which has been estimated at 15 - 25 years shorter than the general population. Obesity and associated metabolic problems, such as hypercholesterolemia and diabetes, are important contributors to cardiovascular disease, represent known side effects of antipsychotic medications, and are highly prevalent in schizophrenia. However, pharmacological treatment options for this patient group are limited given that many FDA-approved weight loss drugs are sympathomimetic, which can raise the risk of psychotic exacerbation. Metformin, an antihyperglycemic that acts in part via glucagon-like peptide-1 to reduce appetite and slow gastric emptying, has been found to safely reduce weight in non-diabetic overweight people with schizophrenia. Our group recently found that 16 weeks of adjunctive metformin led to 2 kg differential weight loss compared to placebo in 146 overweight people with schizophrenia. Because weight loss with metformin is modest, the identification of other safe, non-sympathomimetic options for this population is critical. Lorcaserin is a 5-HT2C agonist recently approved for weight loss. Lorcaserin is associated with ~5.5 kg weight loss compared to baseline and ~3 kg weight loss compared to placebo over 52 weeks in overweight, otherwise healthy adults. The appetite-reducing effect of lorcaserin is mediated in part through melanocortin receptor 4. Given significant weight loss from each of these two drugs with distinct mechanisms of action, this study will build on our preliminary data with metformin to test a strategy of metformin/lorcaserin combination treatment versus lorcaserin monotherapy versus placebo in overweight people with schizophrenia. In non-psychiatric populations, combination treatment has been used successfully for weight loss (i.e., phentermine/topiramate combination treatment) and for other chronic disorders such as hypertension, epilepsy, and diabetes when monotherapy was inadequate. 90 overweight people with schizophrenia (BMI>27) will participate in a 52-week double-blind, randomized study to assess the efficacy and safety of lorcaserin/metformin combination treatment, lorcaserin monotherapy and placebo on weight, body composition, and measures of glucose and lipid metabolism. Behavioral assessments of appetite and plasma levels of key appetite-regulating hormones including leptin, ghrelin and GLP-1 will be measured to examine mechanisms of action of lorcaserin and metformin for weight loss in this population. 24- hour food-recall assessments and accelerometer-based physical activity assessments will help determine the potentially confounding effects of energy intake and expenditure. All subjects will receive a behavioral intervention promoting a healthy diet and increased physical activity. The current proposal will help define new and safe long-term options for treating obesity in people with schizophrenia, critical for this vulnerable population with high rates of obesity and associated cardiovascular morbidity and mortality.